Background and aims: This proposal is designed to improve liposome- directed drug delivery and gene therapy for liver disease with the following specific aims: A. To further characterize properties of asialofetuin (AF)-labeled liposomes, such as entrapping efficiency, as well as defining their potential application in drug-delivery and in liver disease; B. To label cationic liposomes, such as Lipofectin (DOTMA/DOPE), DMRlE/DOPE, and Cytofectin (GS2888/DOPE) with asialofetuin, and to study their biodistribution by intravenous or intraportal administration, C. To evaluate gene transfer efficiency by complexes of AF-labeled cationic liposomes-plasmid DNA in hepatoma cell lines, isolated primary hepatocytes and in mouse liver; D. To test transfection efficiency and the therapeutic potential of complexes of AF-labeled liposomes-alpha 1-antitrypsin ribozymes by intraportal or intravenous administration. Methods: A series of different liposomes and liposome-DNA complexes will be generated, and their efficiency will be evaluated by immunohistochemistry of marker proteins, fluorescent staining techniques, Northern and Western blot analysis, as well as the employment of PCR. Significance: The performance and completion of this program will lead to a better understanding of the process of liposome- mediated-gene transfection, and to the development of novel approaches to target the liver, especially hepatocytes. If successfully undertaken, this proposal has the potential of developing new techniques that may positively affect the treatment of a series of different liver conditions, from alcoholic and metabolic liver disease to hepatocellular carcinoma.